DESCRIPTION: Study of immune response to vaccines is a useful way to evaluate immune competence and to study components of the immune system involved in the specific response. In 2009, when the H1N1 influenza epidemic struck, we investigated a group of virally suppressed HIV-infected patients on combination antiretroviral therapy (cART) for immune responses to the influenza H1N1/09 vaccine, and found that only about 50% mounted a serologic response. We focused on a novel subset of peripheral memory CD4 T cells designated as peripheral (p) T follicular helper cells (Tfh) because of their functional similaritis to Tfh in lymph nodes (LN), including germinal center (GC)-Tfh, that play a critical role in development of memory B cells and plasma cells, inducing antibody affinity maturation, somatic hypermutation and antibody secretion. We found that the pTfh in peripheral blood (PB) of vaccine responders showed expansion post- vaccination and supported antigen specific antibody production from purified autologous B cells only in vaccine responders. Moreover, pTfh were phenotypically and functionally distinct from non-pTfh CD4 T cells. We hypothesize that the pTfh are functionally similar to LN Tfh, and that their impairment results in poor B cell function and deficient antibody production in HIV infected patients. In lymph nodes The Tfh compartment has recently been found to be highly permissive for HIV/SIV infection and replication and these cells undergo expansion in chronic HIV/SIV infection. In preliminary studies we found the pTfh cells in peripheral blood to manifest higher frequencies of inducible HIV as compared to non-pTfh cells in the CD4 T cell compartment of patients on cART. We hypothesize that like the GCTfh, the pTfh cell subset within the CD4 TCM cells is a preferred compartment for HIV infection and replication. A goal of this application is to investigate phenotypic and functional characteristics of pTfh in different clinical situations of HIV infection and to compare them with lymph node Tfh. We have 3 specific aims: 1. To characterize pTfh in HIV infected patients following seasonal influenza vaccination. 2. To characterize pTfh longitudinally in HIV infected patients initiating cART. 3. To examine HIV burden and inducible HIV in pTfh and to compare viruses in pTfh and LN Tfh compartments. This research is significant as circulating pTfh are easily accessible cells that could emerge as promising biomarkers of vaccine responses and as therapeutic targets for manipulating antibody responses and HIV reservoirs.